Association study of DTNBP1 with schizophrenia in a US sample

Abstract

Background Straub et al. (2002b) located a susceptibility region for schizophrenia at the DTNBP1 locus. At least 40 studies (including one study in US populations) attempted to replicate this original finding, but the reported findings are highly diverse and at least five pathways by which dysbindin protein might be involved in schizophrenia have been proposed. The present study aimed to test the association in two common US populations by using powerful analytic methods. Methods Six markers at DTNBP1 were genotyped by mass spectroscopy (“MassARRAY” technique) in a sample of 663 subjects, including 346 healthy subjects [298 European-Americans (EAs) and 48 African-Americans (AAs)] and 317 subjects with schizophrenia (235 EAs and 82 AAs). Thirty-eight ancestry-informative markers (AIMs) were genotyped in this sample to infer the ancestry proportions. Diplotype, haplotype, genotype, and allele frequency distributions were compared between cases and controls, controlling for possible population stratification, admixture, and sex-specific effects, and taking interaction effects into account, using a logistic regression analysis (an extended structured association (SA) method). Results Conventional case-control comparisons showed that genotypes of the markers P1578 (rs1018381) and P1583 (rs909706) were nominally associated with schizophrenia in EAs and in AAs, respectively. These associations became less or non-significant after controlling for population stratification and admixture effects (using SA or regression analysis), and became non-significant after correction for multiple testing. However, regression analysis demonstrated that the common diplotypes (ACCCTT/GCCGCC or GCCGCC/GCCGCC) and the interaction effects of haplotypes GCCGCC × GCCGCC significantly affected risk for schizophrenia in EAs, effects that were modified by sex. Fine-mapping using δ or J statistics located the specific markers (δ: P1328; J: P1333) closest to the putative risk sites in EAs. Conclusions The present study shows that DTNBP1 is a risk gene for schizophrenia in EAs. Variation at DTNBP1 may modify risk for schizophrenia in this population.

Synaptic Dysbindin-1 Reductions in Schizophrenia Occur in an Isoform-Specific Manner Indicating Their Subsynaptic Location

“…Twenty studies on populations across the globe report significant associations between schizophrenia and one or more DTNBP1 SNPs and/or haplotypes (cf. [3]–[6]). An increasing number of studies report that several of these DTNBP1 risk variants are associated with severity of the positive symptoms (e.g., delusions and hallucinations) and especially the negative symptoms (e.g., flattened affect and social withdrawal) of schizophrenia [7]–[10].…”

Neuropsychiatric Illness: A Case for Impaired Neuroplasticity and Possible Quantum Processing Derailment in Microtubules

“…Not all European groups show an association, however; and familial loading, rather than ethnicity, may be the most critical factor (Van Den Bogaert et al, 2003). In agreement with that conclusion, certain variants of the dysbindin-l gene confer increased risk for schizophrenia in European Americans, but not in African Americans or in Koreans (Zuo et al, 2009;Joo et al, 2006).…”

Genomics and epigenomics in novel schizophrenia drug discovery: translating animal models to clinical research and back

“…It is now well known that linkage studies are not exactly well suitable for psychiatric disorders and major problems faced are: small effects of single genes, low number of affected individuals within families, incomplete penetrance, broad diagnostic boundaries and thus difficulty in defining the phenotype [27]. Nevertheless, some of the identified loci in schizophrenia have been persistently replicated and confirmed by more recent genome-wide association studies (GWAS) [28], such as neuregulin 1 (NRG1) [29], dystrobrevin-binding protein 1 [30], disrupted-in-schizophrenia 1 (DISC1) [31], d-amino acid oxidase inhibitor (DAAO) [32] and zinc-finger protein 804A [33].…”